Phencyclidine (PCP), a major drug of abuse, elicits hallucinations and feelings of tranquility and can generate aggressive, violent behavior. Evidence from many laboratories suggests that the effects of PCP and PCP- like drugs in the central nervous system are mediated by PCP receptors. It is now clear that there are at least 3-4 classes of "PCP receptors" and K+- channels. The aim of the proposed research is to determine the molecular structure of the different classes of PCP receptors, their mechanism of action, and their drug selectivity. The specific aims are: 1. To clone and sequence the full-length cDNA coding for each of the four putative NMDA PCP- receptor polypeptides already purified from the rat forebrain by amino-PCP agarose chromatography. 2. To inject the putative PCP-receptor mRNAs synthesized in vitro into Xenopus oocytes and hence to study the expression of functional PCP receptors. 3. To inject the antisense -mRNAs together with total rat brain nRNA into the oocytes and to determine which of the antisense mRNAs will abolish the expression of PCP receptors. 4. To stably express cloned PCP receptor in cell lines lacking endogenous PCP receptors. The experiments described in 1-4, if successful, should enable us to determine the molecular structure of the "high-affinity" PCP/NMDA receptors and also provide information on other classes of PCP receptors.5. To characterize and purify the "low -affinity" PCP receptors of rat brain stem and cerebellum and compare their binding, pharmacological and molecular properties with those of the purified high-affinity receptors from rat forebrain. This information is a prerequisite for (a) future studies aimed at cloning of the low-affinity PCP receptors; (b) elucidation of the relationship between PCP low-affinity sites and the K=+-channel. 6. To characterize the mechanism of action of PCP/NMDA receptor agonists, competitive antagonists, modulators (glycine analogs) and non-competitive blockers (new PCP derivatives and analogs). 7. To identify and map the locality of the PCP-receptor binding sites and regulatory domains and to determine the structure-activity relationships of competitive and non- competitive blockers of the NMDA-channel. Such knowledge will help in the design of selective ligands and novel therapeutic drugs.